HCC: MOLECULAR-TARGETING DRUG THERAPY

Abstract

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer death in Japan. Hepatitis B and/or C virus infection is a major etiology of HCC, thus liver dysfunction due to hepatitis or cirrhosis makes it difficult to decide appropriate treatment for HCC. Cytotoxic agent causes hematological toxic effects easily for these patients due to pancytopenia by liver dysfunction or hypersplenism. Also, cytotoxic chemotherapy is generally ineffective with no established treatment by randomized studies, and local treatment such as trancecatheter arterial infusion chemotherapy has been usually selected even for unresectable cases.

Sorafenib is a multikinase inhibitor that has anti-tumor effect by inhibiting tumor-cell proliferation and tumor angiogenesis. Raf, VEGFRs and PDGFR are the main target of Sorafenib. SHARP trial was multicenter, placebo controlled, randomized trial in patient with advanced HCC. In the study, median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group. Asia–Pacific trial also revealed that sorafenib prolongs overall survival and time to progression.

Major toxic effects of sorafenib are fatigue, hand-foot skin reaction (HFSR), rash, diarrhea, hypertension and liver dysfunction. Especially, HFSR is a troublesome adverse effect that causes patients' discomfort and necessitates a dose reduction of sorafenib. So, the management of HFSR is very important to keep a sufficient dose intensity of treatment. Liver dysfunction is also a significant adverse event of sorafenib. It is important to evaluate the liver function before treatment since safety and efficacy of sorafenib for Child-Pugh B and C patients has not yet been proven.

Sorafenib is expected to show the effectiveness as adjuvant therapy after resection or transarterial chemoembolization. And combination therapies of sorafenib and cytotoxic agents have been evaluated in clinical trials. Several studies which compare sorafenib and other molecular-targeting agents in first-line or which evaluate second-line chemotherapy after sorafenib are also ongoing.